Graphical-model Based Multiple Testing under Dependence, with Applications to Genome-wide Association Studies

TL;DR

This paper introduces a graphical-model-based multiple testing method that leverages dependence structures, using a Markov random field and EM algorithm, improving detection power in genome-wide association studies.

Contribution

It proposes a novel multiple testing procedure based on a Markov random field coupled with an EM algorithm for parameter estimation, enhancing dependence-aware testing.

Findings

Improved multiple testing performance in simulations

Effective control of false discovery rate

Successful application to breast cancer GWAS identifying significant SNPs

Abstract

Large-scale multiple testing tasks often exhibit dependence, and leveraging the dependence between individual tests is still one challenging and important problem in statistics. With recent advances in graphical models, it is feasible to use them to perform multiple testing under dependence. We propose a multiple testing procedure which is based on a Markov-random-field-coupled mixture model. The ground truth of hypotheses is represented by a latent binary Markov random field, and the observed test statistics appear as the coupled mixture variables. The parameters in our model can be automatically learned by a novel EM algorithm. We use an MCMC algorithm to infer the posterior probability that each hypothesis is null (termed local index of significance), and the false discovery rate can be controlled accordingly. Simulations show that the numerical performance of multiple testing can be improved substantially by using our procedure. We apply the procedure to a real-world genome-wide association study on breast cancer, and we identify several SNPs with strong association evidence.